Mir-101-3p downregulation promotes fibrogenesis by facilitating hepatic stellate cell transdifferentiation during insulin resistance

Marica Meroni, Miriam Longo, Veronica Erconi, Luca Valenti, Stefano Gatti, Anna Ludovica Fracanzani, Paola Dongiovanni

Research output: Contribution to journalArticle

Abstract

Insulin resistance (IR) and microRNAs (miRNAs), which regulate cell-to-cell communication between hepatocytes and hepatic stellate cells (HSCs), may intertwine in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The aim of this study was to evaluate whether epigenetics and environmental factors interact to promote progressive NAFLD during IR. We examined the miRNA signature in insulin receptor haploinsufficient (InsR+/−) and wild-type (wt) HSCs by RNAseq (n = 4 per group). Then, we evaluated their impact in an IR-NASH (nonalcoholic steatohepatitis) model (InsR+/− mice fed standard or methionine choline deficient (MCD) diet, n = 10 per group) and in vitro. InsR+/− HSCs displayed 36 differentially expressed miRNAs (p < 0.05 vs. wt), whose expression was then analyzed in the liver of InsR+/− mice fed an MCD diet. We found that miR-101-3p negatively associated with both InsR+/− genotype and MCD (p < 0.05) and the histological spectrum of liver damage (p < 0.01). miR-101-3p was reduced in InsR+/− hepatocytes and HSCs and even more in InsR+/− cells exposed to insulin (0.33 µM) and fatty acids (0.25 mM), resembling the IR-NASH model. Conversely, insulin induced miR-101-3p expression in wt cells but not in InsR+/− ones (p < 0.05). In conclusion, IR combined with diet-induced liver injury favors miR-101-3p downregulation, which may promote progressive NAFLD through HSC and hepatocyte transdifferentiation and proliferation.

Original languageEnglish
Article number2597
JournalNutrients
Volume11
Issue number11
DOIs
Publication statusPublished - Jan 1 2019

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Cell Transdifferentiation
Hepatic Stellate Cells
insulin resistance
Insulin Resistance
Down-Regulation
liver
Choline
MicroRNAs
Methionine
Hepatocytes
fatty liver
Diet
choline
microRNA
cells
hepatocytes
Liver
methionine
Insulin
Insulin Receptor

Keywords

  • Fibrosis
  • HCC
  • Hepatic stellate cells
  • MiR-101-3p
  • NAFLD

ASJC Scopus subject areas

  • Food Science
  • Nutrition and Dietetics

Cite this

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title = "Mir-101-3p downregulation promotes fibrogenesis by facilitating hepatic stellate cell transdifferentiation during insulin resistance",
abstract = "Insulin resistance (IR) and microRNAs (miRNAs), which regulate cell-to-cell communication between hepatocytes and hepatic stellate cells (HSCs), may intertwine in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The aim of this study was to evaluate whether epigenetics and environmental factors interact to promote progressive NAFLD during IR. We examined the miRNA signature in insulin receptor haploinsufficient (InsR+/−) and wild-type (wt) HSCs by RNAseq (n = 4 per group). Then, we evaluated their impact in an IR-NASH (nonalcoholic steatohepatitis) model (InsR+/− mice fed standard or methionine choline deficient (MCD) diet, n = 10 per group) and in vitro. InsR+/− HSCs displayed 36 differentially expressed miRNAs (p < 0.05 vs. wt), whose expression was then analyzed in the liver of InsR+/− mice fed an MCD diet. We found that miR-101-3p negatively associated with both InsR+/− genotype and MCD (p < 0.05) and the histological spectrum of liver damage (p < 0.01). miR-101-3p was reduced in InsR+/− hepatocytes and HSCs and even more in InsR+/− cells exposed to insulin (0.33 µM) and fatty acids (0.25 mM), resembling the IR-NASH model. Conversely, insulin induced miR-101-3p expression in wt cells but not in InsR+/− ones (p < 0.05). In conclusion, IR combined with diet-induced liver injury favors miR-101-3p downregulation, which may promote progressive NAFLD through HSC and hepatocyte transdifferentiation and proliferation.",
keywords = "Fibrosis, HCC, Hepatic stellate cells, MiR-101-3p, NAFLD",
author = "Marica Meroni and Miriam Longo and Veronica Erconi and Luca Valenti and Stefano Gatti and Fracanzani, {Anna Ludovica} and Paola Dongiovanni",
year = "2019",
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doi = "10.3390/nu11112597",
language = "English",
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journal = "Nutrients",
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TY - JOUR

T1 - Mir-101-3p downregulation promotes fibrogenesis by facilitating hepatic stellate cell transdifferentiation during insulin resistance

AU - Meroni, Marica

AU - Longo, Miriam

AU - Erconi, Veronica

AU - Valenti, Luca

AU - Gatti, Stefano

AU - Fracanzani, Anna Ludovica

AU - Dongiovanni, Paola

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Insulin resistance (IR) and microRNAs (miRNAs), which regulate cell-to-cell communication between hepatocytes and hepatic stellate cells (HSCs), may intertwine in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The aim of this study was to evaluate whether epigenetics and environmental factors interact to promote progressive NAFLD during IR. We examined the miRNA signature in insulin receptor haploinsufficient (InsR+/−) and wild-type (wt) HSCs by RNAseq (n = 4 per group). Then, we evaluated their impact in an IR-NASH (nonalcoholic steatohepatitis) model (InsR+/− mice fed standard or methionine choline deficient (MCD) diet, n = 10 per group) and in vitro. InsR+/− HSCs displayed 36 differentially expressed miRNAs (p < 0.05 vs. wt), whose expression was then analyzed in the liver of InsR+/− mice fed an MCD diet. We found that miR-101-3p negatively associated with both InsR+/− genotype and MCD (p < 0.05) and the histological spectrum of liver damage (p < 0.01). miR-101-3p was reduced in InsR+/− hepatocytes and HSCs and even more in InsR+/− cells exposed to insulin (0.33 µM) and fatty acids (0.25 mM), resembling the IR-NASH model. Conversely, insulin induced miR-101-3p expression in wt cells but not in InsR+/− ones (p < 0.05). In conclusion, IR combined with diet-induced liver injury favors miR-101-3p downregulation, which may promote progressive NAFLD through HSC and hepatocyte transdifferentiation and proliferation.

AB - Insulin resistance (IR) and microRNAs (miRNAs), which regulate cell-to-cell communication between hepatocytes and hepatic stellate cells (HSCs), may intertwine in nonalcoholic fatty liver disease (NAFLD) pathogenesis. The aim of this study was to evaluate whether epigenetics and environmental factors interact to promote progressive NAFLD during IR. We examined the miRNA signature in insulin receptor haploinsufficient (InsR+/−) and wild-type (wt) HSCs by RNAseq (n = 4 per group). Then, we evaluated their impact in an IR-NASH (nonalcoholic steatohepatitis) model (InsR+/− mice fed standard or methionine choline deficient (MCD) diet, n = 10 per group) and in vitro. InsR+/− HSCs displayed 36 differentially expressed miRNAs (p < 0.05 vs. wt), whose expression was then analyzed in the liver of InsR+/− mice fed an MCD diet. We found that miR-101-3p negatively associated with both InsR+/− genotype and MCD (p < 0.05) and the histological spectrum of liver damage (p < 0.01). miR-101-3p was reduced in InsR+/− hepatocytes and HSCs and even more in InsR+/− cells exposed to insulin (0.33 µM) and fatty acids (0.25 mM), resembling the IR-NASH model. Conversely, insulin induced miR-101-3p expression in wt cells but not in InsR+/− ones (p < 0.05). In conclusion, IR combined with diet-induced liver injury favors miR-101-3p downregulation, which may promote progressive NAFLD through HSC and hepatocyte transdifferentiation and proliferation.

KW - Fibrosis

KW - HCC

KW - Hepatic stellate cells

KW - MiR-101-3p

KW - NAFLD

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